Constitutive activating mutations of the human luteinizing hormone/chorionic gonadotropin receptor (hLHR) cause familial male-limited precocious puberty (FMPP), a non-central form of gonadotropin-independent precocious puberty. Even though constitutive production of testosterone, which occurs in FMPP patients, is not known to be tumorigenic, we had identified two FMPP patients who developed testicular neoplasia. Another study of testicular tumor also identified an activating mutation of the hLHR in a subgroup of testicular tumor patients. We hypothesize that hLHR with activating mutation turns on genes that ultimately lead to the development of testicular tumor. To study the potential tumorigenic effect of a constitutively activated LHR, we have generated an in vitro cell model. MA-10 cells, a mouse Leydig cell line, were transfected with hLHR carrying activating mutations. The profile of expressed genes in cells expressing the mutated hLHR was compared with that of control cells using cDNA microarrays of the NIH mouse 23K genes. Out of 22,684 genes, 10,353 display high quality informative expression data across all microarray images including MA10 (control) and the experimental samples, in both forward and reverse labeling. The most common activating mutation Asp578Gly induces 42 differentially expressed genes including Bscl2, Tcfe2a, Ercc3, Crsp9, Gabarapl1, Il10rb, and Hsh2. The somatic activating mutation Asp578His found in some patients with testicular tumors induce 74 differentially expressed genes. A number of genes are common between the two treatment groups, including Tcfe2a, Crsp9, and Rpo1-2. All these three genes are involved in transcription. Their relationship with mutated hLHR will be further investigated. The impact of activating mutation of the hLHR has always been considered to be limited to sexual development of the patient. The abnormal social behavior of the patient was thought to be secondary to precocious sexual maturation. Expression of LHR in brain had been demonstrated. We speculate that the abnormal behavior of FMPP patients is caused by the expression of the mutated LHR in the brain. To examine this hypothesis and to study the impact of constitutively activated LHR on spermatogenesis as well as sexual and neurological development, we have generated a transgenic mouse strain that expresses a fusion protein of enhanced green fluorescent protein (EGFP) and hLHR mutant with substitution Asp578Gly or Asp578His. Interestingly, all of the transgenic mice expressing the mutated hLHR are females. The reason for this phenomenon is unclear. We are currently investigating the impact of the mutated receptor on embryonic growth and development. The antithesis of FMPP is Leydig Cell Hypoplasia (LCH). In LCH patients, mutation inactivates the LHR resulting in reduced production of testosterone causing hypergonadotrophic hypogonadism or male pseudohermaphroditism. A novel missense mutation A340T resulting in the substitution of Ile-114 by Phe, which affects one of the Leucine-rich repeats (LRR) in the extracellular domain of the hLHR, has been identified in a patient with LCH. The mutant receptor fails to trigger cAMP production upon hCG stimulation in transient expression studies. This mutation apparently does not affect trafficking of the mutated receptor as revealed by fluorescent microscopic study of the fusion protein of receptor with green fluorescent protein. Instead, it affects binding of the hormone by the receptor. A computer model of the LRR is generated to study the effect of this mutation on the conformation of the receptor. The model clearly demonstrates the conformational effect of the mutations. This finding may be extended to explain the impact of mutations on the biological activities of other proteins with LRRs.